bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2023‒03‒12
fourteen papers selected by
Edmond Chan
Queen’s University, School of Medicine
  1. Fumarate induces vesicular release of mtDNA to drive innate immunity.
  2. Macrophage fumarate hydratase restrains mtRNA-mediated interferon production.
  3. Mitochondrial molecule controls inflammation.
  4. TNIP1 inhibits selective autophagy via bipartite interaction with LC3/GABARAP and TAX1BP1.
  5. Determinants and outcomes of mitochondrial dynamics.
  6. A mitochondrial SCF-FBXL4 ubiquitin E3 ligase complex degrades BNIP3 and NIX to restrain mitophagy and prevent mitochondrial disease.
  7. Optogenetic rejuvenation of mitochondrial membrane potential extends C. elegans lifespan.
  8. Primary cilia sense glutamine availability and respond via asparagine synthetase.
  9. Mitochondrial redox adaptations enable alternative aspartate synthesis in SDH-deficient cells.
  10. Recessive pathogenic variants in MCAT cause combined oxidative phosphorylation deficiency.
  11. Transferred mitochondria accumulate reactive oxygen species, promoting proliferation.
  12. A protein bridge to death between the ER and mitochondria.
  13. The autophagy-NAD axis in longevity and disease.
  14. MitoStores: a place for precursors to ride out the storm.
  1. Nature. 2023 Mar 08.
    Fumarate induces vesicular release of mtDNA to drive innate immunity.
    Vincent Zecchini, Vincent Paupe, Irene Herranz-Montoya, Joëlle Janssen, Inge M N Wortel, Jordan L Morris, Ashley Ferguson, Suvagata Roy Chowdury, Marc Segarra-Mondejar, Ana S H Costa, Gonçalo C Pereira, Laura Tronci, Timothy Young, Efterpi Nikitopoulou, Ming Yang, Dóra Bihary, Federico Caicci, Shun Nagashima, Alyson Speed, Kalliopi Bokea, Zara Baig, Shamith Samarajiwa, Maxine Tran, Thomas Mitchell, Mark Johnson, Julien Prudent, Christian Frezza.
      Mutations in fumarate hydratase (FH) cause hereditary leiomyomatosis and renal cell carcinoma1. Loss of FH in the kidney elicits several oncogenic signalling cascades through the accumulation of the oncometabolite fumarate2. However, although the long-term consequences of FH loss have been described, the acute response has not so far been investigated. Here we generated an inducible mouse model to study the chronology of FH loss in the kidney. We show that loss of FH leads to early alterations of mitochondrial morphology and the release of mitochondrial DNA (mtDNA) into the cytosol, where it triggers the activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)-TANK-binding kinase 1 (TBK1) pathway and stimulates an inflammatory response that is also partially dependent on retinoic-acid-inducible gene I (RIG-I). Mechanistically, we show that this phenotype is mediated by fumarate and occurs selectively through mitochondrial-derived vesicles in a manner that depends on sorting nexin 9 (SNX9). These results reveal that increased levels of intracellular fumarate induce a remodelling of the mitochondrial network and the generation of mitochondrial-derived vesicles, which allows the release of mtDNAin the cytosol and subsequent activation of the innate immune response.
    DOI:  https://doi.org/10.1038/s41586-023-05770-w
  2. Nature. 2023 Mar 08.
    Macrophage fumarate hydratase restrains mtRNA-mediated interferon production.
    Alexander Hooftman, Christian G Peace, Dylan G Ryan, Emily A Day, Ming Yang, Anne F McGettrick, Maureen Yin, Erica N Montano, Lihong Huo, Juliana E Toller-Kawahisa, Vincent Zecchini, Tristram A J Ryan, Alfonso Bolado-Carrancio, Alva M Casey, Hiran A Prag, Ana S H Costa, Gabriela De Los Santos, Mariko Ishimori, Daniel J Wallace, Swamy Venuturupalli, Efterpi Nikitopoulou, Norma Frizzell, Cecilia Johansson, Alexander Von Kriegsheim, Michael P Murphy, Caroline Jefferies, Christian Frezza, Luke A J O'Neill.
      Metabolic rewiring underlies the effector functions of macrophages1-3, but the mechanisms involved remain incompletely defined. Here, using unbiased metabolomics and stable isotope-assisted tracing, we show that an inflammatory aspartate-argininosuccinate shunt is induced following lipopolysaccharide stimulation. The shunt, supported by increased argininosuccinate synthase (ASS1) expression, also leads to increased cytosolic fumarate levels and fumarate-mediated protein succination. Pharmacological inhibition and genetic ablation of the tricarboxylic acid cycle enzyme fumarate hydratase (FH) further increases intracellular fumarate levels. Mitochondrial respiration is also suppressed and mitochondrial membrane potential increased. RNA sequencing and proteomics analyses demonstrate that there are strong inflammatory effects resulting from FH inhibition. Notably, acute FH inhibition suppresses interleukin-10 expression, which leads to increased tumour necrosis factor secretion, an effect recapitulated by fumarate esters. Moreover, FH inhibition, but not fumarate esters, increases interferon-β production through mechanisms that are driven by mitochondrial RNA (mtRNA) release and activation of the RNA sensors TLR7, RIG-I and MDA5. This effect is recapitulated endogenously when FH is suppressed following prolonged lipopolysaccharide stimulation. Furthermore, cells from patients with systemic lupus erythematosus also exhibit FH suppression, which indicates a potential pathogenic role for this process in human disease. We therefore identify a protective role for FH in maintaining appropriate macrophage cytokine and interferon responses.
    DOI:  https://doi.org/10.1038/s41586-023-05720-6
  3. Nature. 2023 Mar 08.
    Mitochondrial molecule controls inflammation.
    Taylor A Poor, Navdeep S Chandel.
      
    Keywords:  Cell biology; Immunology; Metabolism
    DOI:  https://doi.org/10.1038/d41586-023-00596-y
  4. Mol Cell. 2023 Mar 02. pii: S1097-2765(23)00150-8. [Epub ahead of print]
    TNIP1 inhibits selective autophagy via bipartite interaction with LC3/GABARAP and TAX1BP1.
    François Le Guerroué, Eric N Bunker, William M Rosencrans, Jack T Nguyen, Mohammed A Basar, Achim Werner, Tsui-Fen Chou, Chunxin Wang, Richard J Youle.
      Mitophagy is a form of selective autophagy that disposes of superfluous and potentially damage-inducing organelles in a tightly controlled manner. While the machinery involved in mitophagy induction is well known, the regulation of the components is less clear. Here, we demonstrate that TNIP1 knockout in HeLa cells accelerates mitophagy rates and that ectopic TNIP1 negatively regulates the rate of mitophagy. These functions of TNIP1 depend on an evolutionarily conserved LIR motif as well as an AHD3 domain, which are required for binding to the LC3/GABARAP family of proteins and the autophagy receptor TAX1BP1, respectively. We further show that phosphorylation appears to regulate its association with the ULK1 complex member FIP200, allowing TNIP1 to compete with autophagy receptors, which provides a molecular rationale for its inhibitory function during mitophagy. Taken together, our findings describe TNIP1 as a negative regulator of mitophagy that acts at the early steps of autophagosome biogenesis.
    Keywords:  FIP200; FIR; LIR; Selective autophagy; TAX1BP1; TBK1; TNIP1; mitophagy; mitophagy regulation
    DOI:  https://doi.org/10.1016/j.molcel.2023.02.023
  5. Mol Cell. 2023 Feb 28. pii: S1097-2765(23)00115-6. [Epub ahead of print]
    Determinants and outcomes of mitochondrial dynamics.
    Rubén Quintana-Cabrera, Luca Scorrano.
      Mitochondria are not only central organelles in metabolism and energy conversion but are also platforms for cellular signaling cascades. Classically, the shape and ultrastructure of mitochondria were depicted as static. The discovery of morphological transitions during cell death and of conserved genes controlling mitochondrial fusion and fission contributed to establishing the concept that mitochondrial morphology and ultrastructure are dynamically regulated by mitochondria-shaping proteins. These finely tuned, dynamic changes in mitochondrial shape can in turn control mitochondrial function, and their alterations in human diseases suggest that this space can be explored for drug discovery. Here, we review the basic tenets and molecular mechanisms of mitochondrial morphology and ultrastructure, describing how they can coordinately define mitochondrial function.
    Keywords:  cristae; cristae remodeling; fusion fission; mitochondria
    DOI:  https://doi.org/10.1016/j.molcel.2023.02.012
  6. EMBO J. 2023 Mar 10. e113033
    A mitochondrial SCF-FBXL4 ubiquitin E3 ligase complex degrades BNIP3 and NIX to restrain mitophagy and prevent mitochondrial disease.
    Yu Cao, Jing Zheng, Huayun Wan, Yuqiu Sun, Song Fu, Shanshan Liu, Baiyu He, Gaihong Cai, Yang Cao, Huanwei Huang, Qi Li, Yan Ma, She Chen, Fengchao Wang, Hui Jiang.
      Mitophagy is a fundamental quality control mechanism of mitochondria. Its regulatory mechanisms and pathological implications remain poorly understood. Here, via a mitochondria-targeted genetic screen, we found that knockout (KO) of FBXL4, a mitochondrial disease gene, hyperactivates mitophagy at basal conditions. Subsequent counter screen revealed that FBXL4-KO hyperactivates mitophagy via two mitophagy receptors BNIP3 and NIX. We determined that FBXL4 functions as an integral outer-membrane protein that forms an SCF-FBXL4 ubiquitin E3 ligase complex. SCF-FBXL4 ubiquitinates BNIP3 and NIX to target them for degradation. Pathogenic FBXL4 mutations disrupt SCF-FBXL4 assembly and impair substrate degradation. Fbxl4-/- mice exhibit elevated BNIP3 and NIX proteins, hyperactive mitophagy, and perinatal lethality. Importantly, knockout of either Bnip3 or Nix rescues metabolic derangements and viability of the Fbxl4-/- mice. Together, beyond identifying SCF-FBXL4 as a novel mitochondrial ubiquitin E3 ligase restraining basal mitophagy, our results reveal hyperactivated mitophagy as a cause of mitochondrial disease and suggest therapeutic strategies.
    Keywords:  BNIP3/NIX; FBXL4; mitochondrial disease; mitophagy; ubiquitin-proteasome pathway
    DOI:  https://doi.org/10.15252/embj.2022113033
  7. Nat Aging. 2023 Feb;3(2): 157-161
    Optogenetic rejuvenation of mitochondrial membrane potential extends C. elegans lifespan.
    Brandon J Berry, Anežka Vodičková, Annika Müller-Eigner, Chen Meng, Christina Ludwig, Matt Kaeberlein, Shahaf Peleg, Andrew P Wojtovich.
      Mitochondrial dysfunction plays a central role in aging but the exact biological causes are still being determined. Here, we show that optogenetically increasing mitochondrial membrane potential during adulthood using a light-activated proton pump improves age-associated phenotypes and extends lifespan in C. elegans. Our findings provide direct causal evidence that rescuing the age-related decline in mitochondrial membrane potential is sufficient to slow the rate of aging and extend healthspan and lifespan.
    DOI:  https://doi.org/10.1038/s43587-022-00340-7
  8. Nat Metab. 2023 Mar 06.
    Primary cilia sense glutamine availability and respond via asparagine synthetase.
    Maria Elena Steidl, Elisa A Nigro, Anne Kallehauge Nielsen, Roberto Pagliarini, Laura Cassina, Matteo Lampis, Christine Podrini, Marco Chiaravalli, Valeria Mannella, Gianfranco Distefano, Ming Yang, Mariam Aslanyan, Giovanna Musco, Ronald Roepman, Christian Frezza, Alessandra Boletta.
      Depriving cells of nutrients triggers an energetic crisis, which is resolved by metabolic rewiring and organelle reorganization. Primary cilia are microtubule-based organelles at the cell surface, capable of integrating multiple metabolic and signalling cues, but their precise sensory function is not fully understood. Here we show that primary cilia respond to nutrient availability and adjust their length via glutamine-mediated anaplerosis facilitated by asparagine synthetase (ASNS). Nutrient deprivation causes cilia elongation, mediated by reduced mitochondrial function, ATP availability and AMPK activation independently of mTORC1. Of note, glutamine removal and replenishment is necessary and sufficient to induce ciliary elongation or retraction, respectively, under nutrient stress conditions both in vivo and in vitro by restoring mitochondrial anaplerosis via ASNS-dependent glutamate generation. Ift88-mutant cells lacking cilia show reduced glutamine-dependent mitochondrial anaplerosis during metabolic stress, due to reduced expression and activity of ASNS at the base of cilia. Our data indicate a role for cilia in responding to, and possibly sensing, cellular glutamine levels via ASNS during metabolic stress.
    DOI:  https://doi.org/10.1038/s42255-023-00754-6
  9. Elife. 2023 Mar 08. pii: e78654. [Epub ahead of print]12
    Mitochondrial redox adaptations enable alternative aspartate synthesis in SDH-deficient cells.
    Madeleine L Hart, Evan Quon, Anna-Lena B G Vigil, Ian A Engstrom, Oliver J Newsom, Kristian Davidsen, Pia Hoellerbauer, Samantha M Carlisle, Lucas B Sullivan.
      The oxidative tricarboxylic acid (TCA) cycle is a central mitochondrial pathway integrating catabolic conversions of NAD+ to NADH and anabolic production of aspartate, a key amino acid for cell proliferation. Several TCA cycle components are implicated in tumorigenesis, including loss of function mutations in subunits of succinate dehydrogenase (SDH), also known as complex II of the electron transport chain (ETC), but mechanistic understanding of how proliferating cells tolerate the metabolic defects of SDH loss is still lacking. Here, we identify that SDH supports human cell proliferation through aspartate synthesis but, unlike other ETC impairments, the effects of SDH inhibition are not ameliorated by electron acceptor supplementation. Interestingly, we find aspartate production and cell proliferation are restored to SDH-impaired cells by concomitant inhibition of ETC complex I (CI). We determine that the benefits of CI inhibition in this context depend on decreasing mitochondrial NAD+/NADH, which drives SDH-independent aspartate production through pyruvate carboxylation and reductive carboxylation of glutamine. We also find that genetic loss or restoration of SDH selects for cells with concordant CI activity, establishing distinct modalities of mitochondrial metabolism for maintaining aspartate synthesis. These data therefore identify a metabolically beneficial mechanism for CI loss in proliferating cells and reveal how compartmentalized redox changes can impact cellular fitness.
    Keywords:  biochemistry; cancer biology; chemical biology; human
    DOI:  https://doi.org/10.7554/eLife.78654
  10. Elife. 2023 Mar 07. pii: e68047. [Epub ahead of print]12
    Recessive pathogenic variants in MCAT cause combined oxidative phosphorylation deficiency.
    Bryn D Webb, Sara M Nowinski, Ashley Solmonson, Jaya Ganesh, Richard J Rodenburg, Joao Leandro, Anthony Evans, Hieu S Vu, Thomas P Naidich, Bruce D Gelb, Ralph J DeBerardinis, Jared Rutter, Sander M Houten.
      Malonyl-CoA-acyl carrier protein transacylase (MCAT) is an enzyme involved in mitochondrial fatty acid synthesis (mtFAS) and catalyzes the transfer of the malonyl moiety of malonyl-CoA to the mitochondrial acyl carrier protein (ACP). Previously, we showed that loss-of-function of mtFAS genes, including Mcat, is associated with severe loss of electron transport chain (ETC) complexes in mouse immortalized skeletal myoblasts (Nowinski et al., 2020). Here, we report a proband presenting with hypotonia, failure to thrive, nystagmus, and abnormal brain MRI findings. Using whole exome sequencing, we identified biallelic variants in MCAT. Protein levels for NDUFB8 and COXII, subunits of complex I and IV respectively, were markedly reduced in lymphoblasts and fibroblasts, as well as SDHB for complex II in fibroblasts. ETC enzyme activities were decreased in parallel. Re-expression of wild-type MCAT rescued the phenotype in patient fibroblasts. This is the first report of a patient with MCAT pathogenic variants and combined oxidative phosphorylation deficiency.
    Keywords:  MCAT; genetics; genomics; human; mitochondria; mitochondrial disease
    DOI:  https://doi.org/10.7554/eLife.68047
  11. Elife. 2023 Mar 06. pii: e85494. [Epub ahead of print]12
    Transferred mitochondria accumulate reactive oxygen species, promoting proliferation.
    Chelsea U Kidwell, Joseph R Casalini, Soorya Pradeep, Sandra D Scherer, Daniel Greiner, Defne Bayik, Dionysios C Watson, Gregory S Olson, Justin D Lathia, Jarrod S Johnson, Jared Rutter, Alana L Welm, Thomas A Zangle, Minna Roh-Johnson.
      Recent studies reveal that lateral mitochondrial transfer, the movement of mitochondria from one cell to another, can affect cellular and tissue homeostasis1,2. Most of what we know about mitochondrial transfer stems from bulk cell studies and have led to the paradigm that functional transferred mitochondria restore bioenergetics and revitalize cellular functions to recipient cells with damaged or non-functional mitochondrial networks3. However, we show that mitochondrial transfer also occurs between cells with functioning endogenous mitochondrial networks, but the mechanisms underlying how transferred mitochondria can promote such sustained behavioral reprogramming remain unclear. We report that unexpectedly, transferred macrophage mitochondria are dysfunctional and accumulate reactive oxygen species in recipient cancer cells. We further discovered that reactive oxygen species accumulation activates ERK signaling, promoting cancer cell proliferation. Pro-tumorigenic macrophages exhibit fragmented mitochondrial networks, leading to higher rates of mitochondrial transfer to cancer cells. Finally, we observe that macrophage mitochondrial transfer promotes tumor cell proliferation in vivo. Collectively these results indicate that transferred macrophage mitochondria activate downstream signaling pathways in a ROS-dependent manner in cancer cells, and provide a model of how sustained behavioral reprogramming can be mediated by a relatively small amount of transferred mitochondria in vitro and in vivo.
    Keywords:  cancer biology; cell biology; human; mouse
    DOI:  https://doi.org/10.7554/eLife.85494
  12. J Biol Chem. 2023 Mar 03. pii: S0021-9258(23)00223-5. [Epub ahead of print] 104581
    A protein bridge to death between the ER and mitochondria.
    Jialing Lin.
      Commitment to apoptotic cell death occurs at the mitochondria, and is regulated by BCL-2 family proteins localized to this organelle. However, BIK, a resident protein of the endoplasmic reticulum inhibits mitochondrial BCL-2 proteins to promote apoptosis. In a recent paper in the JBC, Osterlund et al. investigated this conundrum. Surprisingly, they discovered that these endoplasmic reticulum and mitochondrial proteins moved toward each other and met at the contact site between the two organelles, thereby forming a 'bridge to death'.
    DOI:  https://doi.org/10.1016/j.jbc.2023.104581
  13. Trends Cell Biol. 2023 Mar 04. pii: S0962-8924(23)00023-5. [Epub ahead of print]
    The autophagy-NAD axis in longevity and disease.
    Niall Wilson, Tetsushi Kataura, Miriam E Korsgen, Congxin Sun, Sovan Sarkar, Viktor I Korolchuk.
      Autophagy is an intracellular degradation pathway that recycles subcellular components to maintain metabolic homeostasis. NAD is an essential metabolite that participates in energy metabolism and serves as a substrate for a series of NAD+-consuming enzymes (NADases), including PARPs and SIRTs. Declining levels of autophagic activity and NAD represent features of cellular ageing, and consequently enhancing either significantly extends health/lifespan in animals and normalises metabolic activity in cells. Mechanistically, it has been shown that NADases can directly regulate autophagy and mitochondrial quality control. Conversely, autophagy has been shown to preserve NAD levels by modulating cellular stress. In this review we highlight the mechanisms underlying this bidirectional relationship between NAD and autophagy, and the potential therapeutic targets it provides for combatting age-related disease and promoting longevity.
    Keywords:  PARP; Parkinson's disease; ageing; mitophagy; neurodegeneration; nicotinamide; sirtuins
    DOI:  https://doi.org/10.1016/j.tcb.2023.02.004
  14. EMBO J. 2023 Mar 06. e113576
    MitoStores: a place for precursors to ride out the storm.
    Megan Balzarini, Zixuan Yuan, Hilla Weidberg.
      The fate of unimported mitochondrial precursors has been increasingly studied in recent years, mostly focusing on protein degradation. In this issue of the EMBO journal, Krämer et al discovered MitoStores, a new protective mechanism that temporarily stores mitochondrial proteins in cytosolic deposits.
    DOI:  https://doi.org/10.15252/embj.2023113576
This page is being maintained by Thomas Krichel. It was last updated on 2023‒03‒12 at 22:16:29.